The University of Chicago (UC) Institute for Translational Medicine (ITM) was created in 2007 to assemble, integrate, and create the intellectual, administrative, and physical resources required to catalyze research and research training in Clinical and Translational Science. Its ultimate goals are to train scientists and health care providers at UC and in our community to determine the molecular, genetic, pathophysiologic and social determinants of disease and disease predisposition in individuals; to test interventions directed toward those mechanisms; and to achieve these goals in a way that is rigorous, efficient, ethical, respectful of, and responsive to our community's needs and values. In its first 4 years, the ITM has capitalized on the outstanding intellectual and physical resources throughout the University and at ITM affiliate Institutions, Argonne National Laboratory, NorthShore University HealthSystem, Illinois Institute of Technology, and Access Community Health Network, and on substantial institutional and CTSA financial investments, to build the infrastructure for a transformative, energized, and self-improving home for clinical and translational research. The impact of the ITM has been greatest in 5 domains: 1) catalyzing the formation of multidisciplinary research teams; 2) establishing a systematic, organized clinical and translational research infrastructure; 3) engaging our community in research; 4) training for careers in clinical and translational team science; and 5) impact on and contributions to the National CTSA Consortium. Building on these, we propose to expand research and training opportunities with five major initiatives: a new T1 Research and Technology Cluster; new Cores in Comparative Effectiveness Research and in Social, Environmental, and non-Biological Determinants of Health; a Personalizing Medicine initiative; a new Entrepreneurship Training and Support Program; and a Nurse-Scientist Training Program at new ITM affiliate Rush University. These programs, strengthened by community advice, engagement, partnership and participation, will ensure continued transformation of clinical and translational science at the University of Chicago and affiliates, on the South Side of Chicago, and beyond.